oxadiazoles and Respiratory-Tract-Infections

We evaluated the efficacy and tolerability of oral pleconaril, an anti-picornavirus agent, in treating acute viral respiratory illness (VRI) in two double-blind, placebo-controlled trials. Otherwise healthy subjects, 14 years of age or older, who presented within 36 h of VRI symptom onset, were randomized to pleconaril 400 mg or matching placebo in liquid (first trial) or tablet (second trial) formulations twice-daily (first trial only) or three-times daily for 7 days. The infected subjects from the corresponding active and placebo groups (three-times daily dosing regimens) were combined for analysis. Among the subset of subjects with proven picornaviral infection in both studies (42% of total enrolled), pleconaril 400 mg three-times daily (n = 323) reduced the time to alleviation of illness (no rhinorrhoea and other symptoms mild or absent for > or = 48 h) compared with placebo (n = 264) (median: 10.0 days for placebo and 8.5 days for pleconaril; P = 0.029). In addition, pleconaril reduced the time to a > or = 50% reduction from baseline in total symptom severity score (median: 4.5 days for placebo and 3.5 days for pleconaril; P = 0.038). Significant reductions in the number of tissues used for nose-blowing (20% reduction) and in nights of disturbed sleep (16% reduction) were also observed. Pleconaril was generally well tolerated; the liquid formulation caused gastrointestinal disturbance in all groups (diarrhoea 10-14%, nausea 5-9%, abdominal discomfort 6-8%), and tablets were associated with a greater incidence of nausea (3% for placebo versus 7% for pleconaril, P = 0.003). Pleconaril 400 mg administered three-times daily reduced the duration and severity of picornaviral VRI in adolescents and adults.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Oxadiazoles; Oxazoles; Picornaviridae Infections; Respiratory Tract Infections; Virus Shedding

A randomized, double-blind study assessed the efficacy and safety of pleconaril, a novel antiviral drug with broad-spectrum activity against picornaviruses, in the treatment of 33 adults with an experimentally induced viral respiratory infection. Subjects received either pleconaril 200 mg twice daily (initial dose of 400 mg) or placebo for 7 days. Fourteen hours after receiving the initial dose of either pleconaril or placebo, subjects were inoculated intranasally with 100 plaque-forming units of coxsackievirus A21. Results revealed statistically significant reductions in viral shedding in nasal secretions (P<.001), nasal mucus production (P=.004), and total respiratory illness symptom scores (P=.013) in pleconaril-treated as compared with placebo-treated subjects. The most common adverse events were nausea and abdominal pain. These data support the safety and efficacy of pleconaril in decreasing the signs and symptoms and viral shedding associated with a viral respiratory infection.

Topics: Adolescent; Adult; Antibodies, Viral; Antiviral Agents; Coxsackievirus Infections; Enterovirus; Female; Humans; Male; Middle Aged; Mucus; Nose; Oxadiazoles; Oxazoles; Respiratory Tract Infections; Virus Shedding

Four unrelated compounds active against rhinovirus were compared in tissue culture, and three of them were used in volunteers challenged with rhinovirus. The compounds were the triazino-indole SKF 40491, the substituted oxadiazole GLR9-338, the imidazo-thiazole RP L9326, and the guanidine derivative ICI 73,602. The abilities of these compounds to reduce the yield of rhinovirus types 3, 4, 9, and 31 from HeLa cells or fibroblasts were compared, and a sensitive serotype was chosen for each challenge experiment in humans. In doubleblind studies volunteers received intranasal medication before and after the challenge. Daily scoring of symptoms and titration of virus in nasal washings showed that subjects treated with SKF, GL, and RP all shed less virus than their corresponding placebo groups, significantly so in the cases of GL and RP. Clinical reactions were also less severe in volunteers treated with RP.

Topics: Adolescent; Adult; Antiviral Agents; Cell Line; Clinical Trials as Topic; Female; HeLa Cells; Humans; In Vitro Techniques; Male; Middle Aged; Oxadiazoles; Respiratory Tract Infections; Rhinovirus; Thiazoles; Urea; Virus Diseases

We investigated the susceptibility of 10 enterovirus D68 (EV-D68) isolates (belonging to clusters A, B, and C) to (entero)virus inhibitors with different mechanisms of action. The 3C-protease inhibitors proved to be more efficient than enviroxime and pleconaril, which in turn were more effective than vapendavir and pirodavir. Favipiravir proved to be a weak inhibitor. Resistance to pleconaril maps to V69A in the VP1 protein, and resistance to rupintrivir maps to V104I in the 3C protease. A structural explanation of why both substitutions may cause resistance is provided.

Topics: Antiviral Agents; Drug Resistance, Viral; Enterovirus D, Human; Enterovirus Infections; Humans; Microbial Sensitivity Tests; Models, Molecular; Oxadiazoles; Oxazoles; Receptors, Drug; Respiratory Tract Infections; Viral Proteins; Virus Replication

NEURAMINIDASE INHIBITORS: Zanamivir, the leading neuraminidase inhibitor has been awarded marketing approval in France for curative treatment of flu. It has been demonstrated that zanamivir reduces the duration of symptoms and the frequency of recourse to antibiotics. INDICATIONS FOR ZANAMIVIR: Besides early prescription for curative treatment of flu, as soon as the first symptoms occur, particularly in vaccinated elderly patients (vaccination is effective in only 70 to 80% of cases), zanamivir could also be used as a preventive treatment in subjects exposed to an index case. EARLY TRIALS WITH PLECONARIL: Pleconaril is active against picomaviruses and appears to have interesting efficacy against exceptionally severe enterovirus infections. Conversely, trials conducted in cases of upper respiratory tract infections and meningitis caused by enteroviruses have shown modest results.

Topics: Antiviral Agents; Drug Approval; France; Guanidines; Humans; Influenza, Human; Neuraminidase; Oxadiazoles; Oxazoles; Picornaviridae Infections; Pyrans; Respiratory Tract Infections; Sialic Acids; Zanamivir

Topics: Aldehydes; Animals; Anti-Inflammatory Agents; Antitussive Agents; Escherichia coli Infections; Klebsiella Infections; Mice; Oxadiazoles; Pyrazoles; Respiratory System; Respiratory Tract Infections; Tetracycline

Topics: Humans; Infant; Otitis; Oxadiazoles; Respiratory Tract Infections; Tetracycline; Tonsillitis

Topics: Anti-Inflammatory Agents; Antitussive Agents; Humans; Oxadiazoles; Respiratory System; Respiratory Tract Infections; Tuberculosis; Tuberculosis, Pulmonary

Topics: Analgesics; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antipyretics; Expectorants; Inflammation; Mice; Oxadiazoles; Research; Respiratory Tract Infections; Tetracycline

Topics: Antitussive Agents; Bronchial Diseases; Bronchitis; Bronchopneumonia; Hemopneumothorax; Humans; Influenza, Human; Lung Diseases; Oxadiazoles; Pleurisy; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Tetracycline

Topics: Antitussive Agents; Humans; Inflammation; Oxadiazoles; Respiratory System; Respiratory Tract Infections; Tetracycline